(1-(4-(3-(p-fluorobenzoyl)-propyl)-1-piperazinyl)-alkyl)-3-alkyl-2-imidazolidinones

ABSTRACT

COMPOUNDS OF THE CLASS OF 1-(2-(4-(3-(P-FLUOROBENZOYL)-ALKYL) - 1 - PIPERAZINYL)-ETHYL) - 3 - ALKYL-2-IMIDAZOLIDINONE WHICH MAY BE SUBSTITUTED IN THE 4-POSITION OF THE IMIDAZOLIDINONE RING BY AN ALKYL GROUP HAVING 1 TO 4 CARBON ATOMS AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE AN ANTI-EMETIC ACTION AND ALSO A MODERATE CENTRAL DEPRESSANT ACTION, E.G. THEY INHIBIT MOTILITY. THEY MOREOVER EXHIBIT NO CATALEPTIC INHERENT ACTION. SUCH COMPOUNDS CAN BE PREPARED FOR INSTANCE BY REACTION OF 1(2-(1-PIPERAZINYL)-ETHYL)-3-METHYL - 2 - IMIDAZOLIDINONE WITH 4 - CHLORO-4&#39;&#39;-FLUOROBUTYROPENONE. THE COMPOUNDS ARE ACTIVE OF INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS.

"United States Patent Office 3,812,126 Patented May 21, 1974 3,812,126[1-[4-[3-(p-FLUOROBENZOYL)-PROPYL] 1 PIPER- AZINYL1-ALKYL] 3 ALKYL 2IMIDAZO- LIDINONES Armin Ziist, Birsfeldeu, Basel-Land, and WalterSchindler,

deceased, by Leonhard Gysin, executor, Riehen, Switzerland, assignors toCiba-Geigy Corporation, Ardsley, N Y

No Drawing. Filed Dec. 1, 1971, Ser. No. 203,870 Claims priority,application Switzerland, Dec. 7, 1970, 18,133/70 Int. Cl.,C07d 51/70 US.Cl. 260-268 H 13 Claims ABSTRACT OF THE DISCLOSURE DETAILED DESCRIPTIONThe present invention relates to new imidazolidinone derivatives, toprocesses for their production, to pharmaceutical compositionscontaining the new compounds, and to the use thereof.

More particularly, the present invention relates to imidazolidinonederivatives of formula I wherein A represents an alkylene group having 2to 3 carbonatoms, A represents an alkylene group having 2 to 4 carbonatoms,

R represents an alkyl group having 1 to 4 carbon atoms,-

and R represents hydrogen, or an alkyl group having 1 to 4 carbon atoms,

and the pharmaceutically acceptable acid addition salts thereof.

As alkylene radicals having 2 to 3 carbon atoms in the compounds offormula I, A and A are: the ethylene, trimethylene or propylene group;and as an alkylene radical having 4 carbon atoms, A is thetetramethylene, the ethyl ethylene, or a methyltrimethylene group.Furthermore, both R and R as an alkyl group are the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or the sec.butyl group- Preferredmembers of this class are:

(1) 1-[2- [4- [3-(p-fluorobenzoyl)-propyl]-1-piperazinyl] -ethyl] -3-methyl-2 imidazolidinone.

(2) 1- [2- [4- [3- (p-fiuorobenzoyl -propyl] -1-piperazinyl]-ethyl] -3-ethyl-2-imidazolidinone.

(3) 1-[2- [4- [3- (p-lfluorobenzoyD-propyl] -1-piperazinyl] -ethyl] -3-n-butyl-2-imidazolidinone.

(4) 1- [3- [4-[3-(p-fiuorobenzoyD-propyl] -1-piperazinyl] -propyl]-3-rnethyI-Z-imidazolidinone.

(5) 1- [2- [4- [3- (p-fiuorobenzoyl) -propyl]-1-piperazinyl]-ethyl]-3-isopropyl-2-imidazolidinone.

(6) 1- [3- [4- [3 (p-fluorobenzoyl) -propyl]-1-piperazinyl] -propyl]-3-ethyl-2-imidazolidinone.

and the pharmaceutically acceptable acid addition salts thereof.

Compounds of the formula I and the pharmaceutically acceptable acidaddition salts thereof have valuable pharmacological properties and ahigh therapeutic index.

In the case of oral, rectal or parenteral administration, they have ananti-emetic action, as was determined in the apomorphine-vomiting testin the case of the dog and the golden hamster; the said compounds alsohave a moderate central depressant action, e.g. they inhibit motility.They moreover exhibit no cataleptic inherent effect. These properties,which can be shown by selected standard tests [cp. W. Theobald et al.,Arzneimittelforsch, 17, 561 (1967)], characterize the said compounds asbeing suitable for the treatment of emesis of varying origin, and ofpsychosomatic disturbances.

The test results indicated in the following table are illustrative, andillustrative only, of the pharmaceutical activity of the subjectcompounds. The compounds 1 to 6 in the table are the compounds 1 to 6listed above, compounds 1 to 3, 5 and 6 being for the purposes oftesting in the form of their dihydrochloride salt and compound 4 in theform of its bis-maleate salt.

TABLE Antagonistic activity in the apomorphine- 50% Adrenolytic vomitingtest a desrease of activity on orientation isolated Golden Compound No.motility l organs 1 hamster Dog l After i.p. administration on mice;dose in mg./kg. 5 In comparison with RE GITIN=1. l Caused by s.c.application, dose ED 50 in mg.,lkg., 30 minutes before 5.0. applicationof 0.1 mg./kg. of apomorphiue-hydroehloride. Compounds of the formula Iare produced in the caseof the first process according to the inventionby the reaction of compounds of formula II:

wherein A A R and R have the meanings given under.

formula I, or of the alkali metal derivative of such a compound, with areactive ester of 3-(p-fluorobenzoyl)-propanol. The product may,optionally, be converted with an inorganic or organic acid into anaddition salt.

Suitable reactive esters of 1-(p-fiuorobenzoy1)-propanol are, forexample, halides such as the chloride orbromide, also sulphonic acidesters, e.g. the methanesulphonic acid ester, or the oorp-toluene-sulphonic acid ester. These esters are reacted with the freebases of the formula II preferably in the presence of a solvent.Suitable solvents are those which are inert under the reactionconditions, e.g. hydrocarbons such as benzene or toluene, halogenatedhydrocarbons such as chloroform, ethereal liquids such as ether ordioxane, as well as lower alkanones, particularly diethyl ketone.

In the reaction according to the invention of one molecular equivalentof reactive ester with one molecular .3 equivalent of free base, onemolecular equivalent of acid is split off. This acid can be bound toexcess base of the formula II, or to the dibasic reaction product.Preferably, however, an acid-binding agent is added to the reactionmixture. Suitable acid-binding agents are, e.g. alkali metal carbonatessuch as sodium or potassium carbonate, also tertitry organic bases suchas, e.g. pyridine, triethylamine or diisopropylethylamine. Excesstertiary bases may also be used as solvent.

Optionally, the reaction can be accelerated by an alkali iodide,especially potassium iodide. The reaction is performed at ca. 50 to 1500., preferably at the boiling point of the solvent.

If for the reaction according to the invention is used, instead of thefree base of the formula II, an alkali metal derivative thereof, e.g. asodium, potassium or lithium derivative, then it is advantageous for thereaction to be performed in a hydrocarbon e.g. in benzene or toluene.

The formation of the alkali metal derivatives of the first reactioncomponent is effected preferably in situ, e.g. by the addition of atleast one molecular equivalent of alkali metal hydride, alkali metalamide or of an alkali metal organic compound, when starting with onemolecular equivalent of a free base. For example, as alkali metal amidesare used sodium and lithium amide, as alkali metal hydrides is usedsodium hydride, and as alkali metal organic compound phenyllithium orbutyllithium.

Examples of compounds of the formula II which are known are, e.g.1-[2-(1-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone, 1[3-(l-piperazinyl)-propyl]-3-methyl- 2-imidazolidinone, as well as thecorresponding 3-ethyl compounds; they can be produced by variousprocesses. Further compounds of this type can be obtained analogously.

Of the reactive esters suitable as the second reaction component,4-chloro-4'-fluorobutyrophenone [cp. C. van de Westeringh et al., Ind.chim. belge, 25, 1073 (1960)], for example, is described in theliterature.

In a second process according to the invention compounds of the generalformula I are produced by reacting a compound of the formula III:

wherein A has the meaning stated under formula I, or an alkali metalderivative thereof with a reactive ester of a compound of the formulaIV:

I'M CHz-CH HO-Ar-N N-R II (IV) wherein A R and R have the meaning givenunder formula I, followed by optional conversion of the obtained productwith an inorganic or organic acid into an addition salt.

Suitable reactive esters of the compounds of the formula IV are, e.g.halides such as chlorides or bromides,

also sulphonic acid esters, e.g. the methanesulphonic acid ester or the0- or p-toluene-sulphonic acid ester.

The reaction according to the invention of the free bases, or of theiralkali metal derivatives can be performed in the same solvents ordiluents, and at the same reaction temperatures, as in the firstprocess. With the condensation of one molecular equivalent of free basewith one molecular equivalent of reactive ester, one molecularequivalent of free acid is split off, which can be bound to the sameacid-binding agents as in the case of the first process.

The alkali metal derivatives of the first reaction component, e.g.sodium, potassium or lithium derivatives,

are preferably used in situ in the process according to the invention.These alkali metal derivatives can be obtained in a manner analogous tothat for the alkali metal derivatives of the first process.

Of the bases embraced by the formula III, 4'-fluoro-4-(l-piperazinyl)-butyrophenone is known. Further compounds of this typecan be produced analogously.

The second reaction component of the process according to the inventionis the reactive esters of compounds of the formula IV. Of thesecompounds, 1-(2-chloroethyland l-(3chloropropyl)-3-methyl-2-imidazolidinone, as well as1-(2-chloroethyl)-3-butyl-2-imidazolidinone, are, for example, known,and can be produced by various processes. Further compounds of this typecan be produced analogously.

Compounds of the formula I of which the radical A is an ethylene groupcan be produced by a third process according to the invention by thereaction of a compound of the previously given formula III, wherein Arepresents an alkylene group having 2 to 3 carbon atoms, or an alkalimetal derivative thereof, with a compound of the general formula V:

wherein R represents an alkyl group having 1 to 4 carbon atoms,

R represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and

Y represents halogen,

or with an alkali metal derivative of such a compound; and, followed byoptional conversion of an obtained product with an inorganic or organicacid into an addi tion salt.

The radical Y of the general formula V is a halogen, preferably chlorineor bromine.

The reaction according to the invention of the free bases of the formulaIII, or of their alkali metal derivatives, with the urea derivatives ortheir alkali metal derivatives can be performed in the same solvents ordiluents, and at the same reactiontemperatures, as in the case of thefirst process. With the reaction of one molecular equivalent of freebase with one molecular equivalent of the free urea derivatvie, twomolecular equivalents of hydrogen halide are split off, which can alsobe bound to the same acid-binding agents. Both reaction components areused as alkali metal derivatives, e.g. sodium, potassium or lithiumderivatives, preferably in situ, in the process according to theinvention. These alkali metal derivatives can be obtained analogously tothe alkali metal derivatives of the first process.

The preparation of the starting materials of the formula III isdescribed following the second process. A starting material embraced bythe general formula V is 1-methyl-3,3-bis-(2-chloroethyl)-urea, whichcan be obtained starting with diethanolamine. Diethanolamine yields,with l-methylisocyanate: l-methyl-3,3-bis-(2-hydroxyethyD-urea, whichreacts with thionyl chloride with elimination of sulphur dioxide andhydrogen chloride. Further starting materials of the formula V can beproduced analogously.

According to a fourth process, compounds of the formula I are producedby the reaction, according to Grignard, of a compound of the generalformula VI:

with a compound of the formula VII:

(VII) wherein A A R and R have the meaning given under under formula I,and one of the two groups X or Z represents a nitrile or carbonylhalidegroup, and the other a magnesium halide radical (MgHal), zinc halideradical (ZnHal), or a metal-organic cadmium radical; with optionalconversion of the obtained product with an inorganic or organic acidinto an addition salt.

The halides used in the process are preferably chlorides, bromides oriodides.

As metal-organic cadmium radical, X is e.g. the group VIII:

/CHz-CH; CHI-C H Cd(CH2) a-N N-Ar-N N-R (5 (VIII) wherein A A R and Rhave the meaning given under formula I, and Z the group IX:

The zinc halide compounds and the cadmium organic compounds arepreferably reacted with carbonyl halides, and the magnesium halidecompounds preferably with nitriles.

The process according to the invention is carried out under the usualconditions of the Grignard reaction at ca. 0 to 140 C. The usualethereal solvents suitable for the preparation of the magnesium-organiccompounds, such as ether, dibutyl ether or tetrahydrofuran, can be usedas reaction media. Optionally, hydrocarbons, such as benzene or toluene,can be added to these solvents, and the reaction temperature raised,towards the end of the reaction, by the distilling off of the ether. Thedecomposition of the direct reaction products is effected in the usualmanner, e.g. with the aid of water and dilute hydrochloric acid.

Of the starting materials embraced by the general formula VI, it ispossible to produce, for example, compounds of which the symbols X and Arepresent MgCl and CH CH respectively, as follows: Starting withl-piperazinepropanol [cp. S. M. McElvain and L. W. Bannister, J. Am.Chem. Soc., 76, 1126 (1954)], this is condensed, in the presence ofpotassium carbonate, with a chloride of a compound of the formula IV.The condensation product is a compound embraced by the formula VI ofwhich the symbols X and A are -OH and CH CH resp. The obtained compoundis converted into the dihydrochloride and transformed with thionylchloride into the corresponding compound of which the radical X ischlorine. The chloride is subsequently reacted with magnesium accordingto Grignard. Further compounds of this type can be produced analogously.

Also embraced by the formula VI are compounds of which the symbols X andA are CN and CH CH respectively. Such compounds can be produced, e.g.from the corresponding chlorides, the preparation of which has alreadybeen described, by means of calcium cyanide.

The starting compounds embraced by the formula VII of which compoundsthe symbol Z is CN or MgBr are described in the literature. The startingmaterial embraced by the general formula VII and of which the symbol Zis the group IX can be produced as follows: Starting withp-fluorophenylmagnesium bromide, this is reacted in an ethereal solutionwith cadmium chloride.

The compounds of the formula I obtained by the processes according tothe invention are, optionally, subsequently converted in the usualmanner into their addition salts with inorganic and organic acids. Forexample, to a solution of a compound of the formula I in an organicsolvent is added the acid desired as salt component, or a solution ofthe acid. Preferably chosen for the reaction are organic solvents, inwhich the formed salt is difficultly soluble, so that it can beseparated by filtration. Such solvents are, e.g. methanol, acetone,methyl ethyl ketone, acetone/ether, acetone/ethanol, methanol/ether orethanol ether.

For use as pharmaceutical compositions, it is possible to use, insteadof free bases, pharmaceutically acceptable acid addition salts, i.e.salts with such acids of which the anions are not toxic in the case ofthe dosage amounts in question. It is moreover of advantage if the saltsto be used as pharmaceutical compositions, crystallize well and are not,or only slightly, hygroscopic. For salt formation with compounds of theformula I, it is possible to use, e.g. hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, Z-hydroxyethanesulphonic acid, acetic acid, malicacid, tartaric acid, citric acid, lactic acid, oxalic acid, succinicacid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid, mandelic acid and embonic acid.

As previously mentioned, the new active substances are administeredorally, rectally or parenterally. The dosage depends on the manner ofadministration, on the species, on the age, and on the individualcondition. The daily dosages of the free bases, or of pharmaceuticallyacceptable salts thereof, vary between 0.15 mg./kg. and 10.5 mg./ kg.for warm-blooded animals. Suitable dosage units such as drages, tablets,suppositories or ampoules, preferably contain 5-200 mg. of an activesubstance according to the invention.

I Dosage units for oral administration contain as active substancepreferably between 10-90% of a compound of the formula I, or of apharmaceutically acceptable salt thereof. They are produced by combiningthe active substance, e.g. with solid pulverulent carriers such aslactose, saccharose, sorbitol, mannitol; starches such as potato starch,maize starch or amylopectin, also laminaria powder or citrus pulppowder; cellulose derivatives or gelatine, optionally with the additionof lubricants such as magnesium or calcium stearate, or polyethyleneglycols, to form tablets or drage cores. The drage cores are coated, egwith concentrated sugar solutions which may also contain, e.g. gumarabic, talcum and/or titanium dioxide; or with a lacquer dissolved inreadily volatile organic solvents or mixtures of solvents. Dyestuffs canbe added to these coatings, e.g. to distinguish between varying dosagesof active substance.

Further dosage units suitable for oral administration are hard gelatinecapsules, as Well as soft closed capsules made from gelatine and asoftener, such as glycerin. The hard capsules preferably contain theactive substance as a granulate, e.g. in admixture with fillers such asmaize starch, and/or lubricants such as talcum or magnesium stearate,and optionally stabilizers such as sodium metabisulphite (N21 S O orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as polyethylene glycols,whereby stabilizers may also be added.

Suitable dosage units for rectal administration are, e.g.

suppositories consisting of a combination of an active substance with asuppository base material. Suitable suppository base materials are, e.g.natural or synthetic triglycerides, parafiin hydrocarbons, polyethyleneglycols, or higher alkanols. Also suitable are gelatine rectal capsulesconsisting of a combination of the active substance with a basematerial. Suitable as a base material are, e.g. liquid triglycerides,polyethylene glycols, or parafiin hydrocarbons.

Ampoules for parenteral administration, especially intramuscularadministration, preferably contain a watersoluble salt of an activesubstance in a concentration of preferably 0.5-5%, optionally togetherwith suitable stabilizers and buffer substances, in aqueous solution.

The following prescriptions further illustrate the production oftablets, drages, capsules, suppositories and ampoules:

(a) 250 g. of 1-[2-[4-[3-(p-fluorobenzoyl)-propyl]1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone are mixed with 175.8 g.of lactose and 169.70 g. of potato starch; the mixture is then moistenedwith an alcoholic solution of g. of stearic acid, and granulated througha sieve. After drying of the granulate, 160 g. of potato starch, 200 g.of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicondioxide are mixed in; the mixture is subsequently pressed into 10,000tablets each weighing 100 mg. and each containing 25 mg. of activesubstance. The tablets can, if required, be provided with grooves for amore precise adjustment of the dosage amount.

(b) A granulate is produced from 250 g. of 1-[2-[4-[3-(p-fluorobenzoyl)-propyl] 1 piperazinylJ-ethyl] 3-methyl-2-imidazolidinone-dihydrochloride, 175.90 g. of lactose, and thealcoholic solution of 10 g. of stearic acid. After drying of thegranulate, it is mixed with 56.60 g. of colloidal silicon dioxide, 165g. of talcum, g. of potato starch and 2.50 g. of magnesium stearate; themixture is then pressed into 10,000 drage cores. These are subsequentlycoated with a concentrated syrup made from 502.28 g. of crystallizedsaccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestufland 1.5 g. of titanium dioxide; they are then dried. The obtained drageseach weigh 120 mg. and each contain mg. of active substance.

(c) To produce 1000 capsules each containing 25 mg. of active substance,25 g. of 1-[2- [4-[3-(p-fiuorobenzoyl)-propyl]-1-piperazinyl]-ethyl]-3-methyl 2 imidazolidinone are mixed with248.0 g. of lactose; the mixture is evenly moistened with an aqueoussolution of 2.0 g. of gelatine, and then granulated through a suitablesieve (e.g. sieve III, Ph. Helv. V). The granulate is mixed with 10.0 g.of dried maize starch and 15.0 g. of talcum; the mixture is then evenlyfilled into 1000 hard gelatine capsules, size 1.

(d) A suppository base mixture is prepared from 2.5 g. of1-[2-[4-[3-(p-fiuorobenzoyl)propyl]-l-piperazinynethyl]-3-methyl-2-imidazolidinone and 167.5 g. ofadeps solidus; the mixture is then filled into 100 suppositories eachcontaining 25 mg. of active substance.

(e) A solution of 25 g. of 1-[2-[4-[3-(p-fluorobenzoyl)-propyl]-l-piperazinyl]-ethyl]-3-methyl 2 imidazolidinone-dihydrochloridein one litre of water is filled into 1000 ampoules, and then sterilized.An ampoule contains a 2.5% solution of 25 mg. of active substance.

Tablets, drages, capsules, suppositories and ampoules can be producedaccording to the same directions if, instead of 1- [2- [4-3-(p-fiuorobenzoyl) -propyl]-1-piperazinyl]-ethyl]-3-methyl 2imidazolidinone, the identical amounts are used of 1- [2-[4-[3-(p-fluorobenzoyl)propyl]- l-piperazinyl]-ethyl]-3-butyl 2imidazolidinone or of its dihydrochloride.

The following examples further illustrate the production of the newcompounds of the formula I and of intermediates not hitherto described;the said examples do not, however, in any way restrict the scope of theinvention. The temperatures are given in degrees centigrade; and silicagel, Merck, particle size 0.05-0.2 mm., is employed for the elutionchromatography.

EXAMPLE 1 21.2 g. (0.1 mole) of 1-[2-(l-piperazinyl)-ethyl]-3-inethyl-2-imidazolidinone, 24.0 g. (0.12 mole) of4-chloro-4'-fluorobutyrophenone [cp. C. van de Westeringh et a1., Ind.chim. belge, 25, 1073 (1960) 27.6 g. (0.2 moles) of finely powderedpotassium carbonate and 16.6 g. (0.1 mole) of powdered potassium iodideare introduced into 200 ml. of diethyl ketone. The obtained mixture isrefiuxed for hours, and then filtered through Celit No. 545 (trade nameof Johns Manville International Corp., New York). The filter residue isafterwards washed with acetone, and the filtrate concentrated in vacuo.The residue is taken up in benzene, the benzene solution washed withwater, and extracted with 2 N hydrochloric acid. The pH-value of theaqueous extract is adjusted to 13 with concentrated sodium hydroxidesolution, and the precipitated free base is taken up in benzene. Thebenzene solution is washed with water, dried over magnesium sulphate,and concentrated in vacuo. The residue is recrystallized frombenzene/petroleum ether. The obtained pure1-[2-[4-[3-(p-fiuorobenzoyl)-propyl] 1piperazinyl]-ethyl]-3-methyl-2-imidazolidinone melts at 92-93".

An amount of 3.7 g. (0.01 mole) of the obtained free base is dissolvedin 5 ml. of acetone; to the solution is then added ethereal hydrochloricacid until an acid reaction is obtained on a Congo red indicator. Theprecipitated dihydrochloride hemihydrate melts at 226-230".

EXAMPLE 2 The following final products are obtained, analogously toExample 1, starting with 15.0 g. (0.075 moles) of 4- chloro-4-fluorobutyrophenone:

(a) With 11.3 g. (0.05 moles) of 1-[2-(1-piperazinyl)-ethyl]-3-ethyl-2-imidazolidinone is obtained: 1-[2-[4-[3-(p-fluorobenzoyl)-propyl]-l piperazinyl]-ethyl]-3-ethyl-2-imidazolidinone, M.P. -67"; M.P. of the dihydrochloride-hemihydrate:23 6-23 8 (b) With 12.7 g. (0.05 moles) of 1-[2-(1-piperazinyl)-ethyl]-3-butyl 2 imidazolidinone is obtained: crude 1- [2-[4-[3-(0fluorobenzoyD-propyl] l piper-azinyl]- ethyl]-3-butyl- 2imidazolidinone, which is purified by means of elution chromatography. Acolumn of 200 g. of basic silica gel is employed which has previouslybeen impregnated with 0.5 N aqueous sodium hydroxide and again dried.Benzene/methanol (100:1) is used as the elution agent. The eluate isconcentrated in vacuo, the residue dissolved in acetone, and to thesolution then added ethereal hydrochloric acid until an acid reaction isindicated on a Congo red indicator. The precipitated dihydrochloride isrecrystallized from ethanol/ethyl acetate; it melts at 235-237;

(0) With 12.0 g. (0.05 moles) of 1-[2-(1-piperazinyl)-ethyl]-3-isopropyl 2 imidazolidinone is obtained: 1-[2- [4- [3-(p-fluorobenzoyl) -propyl] l-piperazinyl] -ethyl] -3-isopropyl-2-imidazolidinone, M.P. 61-64"; M.P. of the dihydrochloride:247-250 (d) With 11.3 g. (0.05 mole) of 1-[3-(l-piperazinyl)-propyl]-3-methyl-2-imidazolidinone is obtained: crude 1-[3-[4-[3-(p-fluorobenzoyl)-propyl] 1piperazinyH-propyl]-3-methyl-2-imidazolidinone; the crude base isdissolved in 50 ml. of acetone, and to the solution is then added asolution of maleic acid in acetone until an acid reaction is obtained,whereupon ether is added. The precipitated 1-[3-[4-[3-(p-fluorobenzoyl)propyl]-1-piperazinyl]-propyl1-3-methyl 2 imidazolidinone-dimaleate isrecrystallized from ethanol/ethyl acetate; it melts at 164-166;

(e) With 12.0 g. (0.05 moles) of 1-[3-(1-piperazinyl)- propyl]-3-ethyl-2-imidazolidinone is obtained: crude 1-[3-[4-[3-(p-fluorobenzoyl)-propyl] 1piperazinyl]-propyl]-3-ethyl-Z-imidazolidinone; M.P. of thedihydrochloride=244-246 and (f) With 13.40 g. (0.05 moles) of1-[3-(1-piperazinyl)- propyl]-3-butyl-2-imidazolidinone is obtained:crude 1-[3- I [4-[3-(p-fluorobenzoyl)-propyl] 1piperazinylJ-propyl]-3-butyl-2-imidazolidinone; M.P. of thedihydrochloride=236-240.

EXAMPLE 3 (a) From 11.3 g. (0.05 moles) of1-[2-(hexahydrolH-1,4-diazepin-1-y1)-ethyl] -3 -methyl-2-imidazolidinoneand 15 .0 g. (0.075 moles) of 4-chloro-4'-fluorobutyrophenone isobtained, analogously to Example 1(a), crude 1- [2-[4-[3-(p-fluorobenzoyl) -propyl]-hexahydro-1H-1,4-diazepin-1-yl]-ethyl]-3methyl-2-imidazolidinone, which is purified on acolumn of 200 g. of basic silica gel (impregnated with sodium hydroxide)by elution chromatography.

9 The elution agent used is benzene/methanol (100:2). The eluate isconcentrated in vacuo, the residue (8.0 g.) dissolved in acetone, andthe dimaleate precipitated with 4.63 g. (0.04 moles) of maleic acid. Thedimaleate is recrystallized from methanol/ ethyl acetate, whereupon itmelts at 104-106.

The starting product is produced as follows:

(b) 17.2 g. (0.1 mole) of hexahydro-1H-l,4-diazepinel-carboxylic acidethyl ester [cp. R. B. Angier et al., J. Med. Chem. 11, 720 (1968), 19.4g. (0.12 moles) of 1-(2- chloroethyl)-3-methyl-2-imidazolidinone and27.6 g. of potassium carbonate are refluxed in 50 ml. of diethyl ketonefor 24 hours. The hot reaction mixture is then filtered through purifieddiatomaceous earth, the filter residue extracted three times withbenzene, and the combined filtrates concentrated in vacuo. The oilyresidue is distilled in high vacuum. The obtained4-[2-(2-oxo-3-methyl-1-imidazolidinyl)-ethyl]-hexahydro-lH-l,4-diazepine-l-carboxylic acidethyl ester boils at 170-180/0.01 torr; n

An amount of 25.0 g. (0.084 moles) of the compound obtained according to(b) is refluxed with 200 ml. of abs. ethanolic potassium hydroxidesolution (20 g. of potassium hydroxide to 100 ml. of solution) for 20hours. The reaction mixture is then cooled and concentrated in vacuo.The residue is taken up in benzene and water, and the organic phaseseparated; the aqueous phase is saturated with potassium carbonate andextracted with benzene. The benzene extract is dried over potassiumcarbonate, the solvent evaporated oil in vacuo, and the oily residuedistilled in high vacuum. The pure 1-[2-(hexahydro1H-l,4-diazepin-l-yl)-ethy1]-3-methyl-2-imidazolidinone boils at125128/0.01 torr; n 1.5163.

EXAMPLE 4 From 11.3 g. (0.05 moles) of1-[2-(3-methyl-1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone and 15g. (0.075 moles) of 4 chloro-4'-fluorobutyrophenone is obtained,analogously to Example 3(a), 1-[2- [4-[3-(p'fluorobenzoyl) propyl]3-methyl-1-piperazinyl]-ethyl]-3-methy1-2- imidazolidinone-dimaleate.The starting material, 1-[2-(3- methyll-piperazinyl) -ethyl]-3-methyl-2-imidazolidinone, B.P. 142/ 0.01 torr, n 1.5115, is producedanalogously to Example 3. (b-c). Starting with3-methyl-1-piperazinecarboxylic acid ethyl ester [cp. J. C. Dulf and D.K. Jung, Can. Pharm. 1., 95, 256 (1962)], the intermediate 4-[2- (2 oxo3-methyl-1-imidazolidinyl)-ethyl]-3-methyl-1- piperazine-carboxylic acidethyl ester is obtaied, B.P. 170 180/0.01 torr; n 1.4996.

EXAMPLE 5 An amount of 25.0 g. (0.1 mole) of 4-fluoro-4-( 1-.piperazinyl)-butyrophenone is refluxed with 19.4 g. (0.12 moles) of 1(2-chloroethyl)-3-methyl-2-imidazolidinone and 27.6 g. (0.2 moles) ofpotassium carbonate in 200 ml. of diethyl ketone for 24 hours. The hotreaction mixture is filtered through purified diatomaceous earth, theresidue washed three times with hot benzene, and the combined filtratesconcentrated in vacuo. The oily residue is taken up in benzene, thebenzene solution washed with water, and extracted with 2 N hydrochloricacid. The .acid aqueous extract is then rendered alkaline withconcentrated sodium hydroxide solution, and the precipitated free baseextracted with benzene. The benzene solution is washed with water, driedover magnesium sulphate,

vandconcentrated in vacuo. The obtained residue is re- EXAMPLE 6 v Thefollowing final product is obtained analogously to Example 5:

.. From 25.0 g. 0.1 mole) of 4'-fluoro-4-(l-piperazinyl)-'butyropheno'ne and 25.7 g. (0.12 moles) of"1-(2-chloroethyl-3-butyl-2-imidazolidinone is obtained: crude 1-[2- 10[4 [3-(p-fluorobenzoyl)-propyl]-1-piperazinyl]-ethyl]-3-butyl-Z-imidazolidinone, which is purified through a column of 400 g. ofbasic silica gel by means of elution chromatography. The eluant used isbenzene/methanol (:1). The purified base is converted, analogously toExample 2(b), into its dihydrochloride which, after recrystallizationfrom ethanol/ethyl acetate, melts at 235- 237.

EXAMPLE 7 (a) An amount of 12.5 g. (0.05 moles) of 4'-fluoro-4-(l-piperazinyl)-butyrophenone is refluxed with 11.9 g. (0.06 moles) ofl-methyl-3,3 bis-(2-chloroethyl)-urea and 27.6 g. (0.2 moles) ofpotassium carbonate in 200 ml. of diethyl carbonate for 16 hours. Thehot reaction mixture is then filtered through purified diatomaceousearth, the filler residue washed with hot benzene, and the combinedfiltrates are concentrated in vacuo. The residue is dissolved inbenzene, the benzene solution extracted with 2 N hydrochloric acid, theacid aqueous extract made alkaline with concentrated sodium hydroxidesolution, and the precipitated free base extracted by being shaken withbenzene. The benzene extract is washed with water, dried over magnesiumsulphate, and the benzene evaporated oil under vacuum. The residue ischromatographed on a column of 200 g. of basic silica gel,benzene/methanol (100:2) being used as eluant. The fractions containingthe crude product are concentrated by evaporation, and the residue isrecrystallized from benzene/petroleum ether. The obtained pure1-[2-[4-[3-(pfluorobenzoyl) propyl]-1-piperazinyl]-ethyl]-3-methyl-Z-imidazolidinone melts at 92-93.

The 1-methyl-3,3-bis-(2-chloroethyl)-urea required as starting materialis produced as follows:

(b) An amount of 105.1 g. (1.0 mole) of freshly distilled diethanolamineis dissolved in 1000 ml. of absolute methylene chloride. To thissolution are added dropwise at 10, in the course of one hour, 59.0 g.(1.03 moles) of methylisocyanate dissolved in 2.00 ml. of absolutemethylene chloride. The reaction mixture is refluxed for minutes andthen cooled to 0; to the obtained solution' of1-methyl-3,3-'bis-(2-hydroxyethyl)-urea is then added dropwise, in thecourse of one hour, a solution of 250 g. (2.1 moles) of thionyl chloridein 250 ml. of absolute methylene chloride. The reaction mixture isafterwards refluxed for 4 hours, concentrated in vacuo,

'and the residue, crude 1-methyl-3,3-bis-(2-chloroethyl)- urea, driedfor 8 hours at 70-'80 under high vacuum.

EXAMPLE 8 (a) Th'e'following final product is produced analogously toExample 7: 7 From 12.5 g. (0.05 moles) of4'-fluoro-4-(1-piperaziny1)-butyrophenone and 14.5 g. (0.06 moles) of 1--butyl-3,3-bis-(2-chloroethyl) urea is obtained: 1-[2-[4- tilleddiethanolamine is dissolved in 1000 ml. of absolute methylene chloride.To this solution are added dropwise at 10, in the course of one hour,101.9 g. (1.03 moles) of butylisocyanate dissolved in 200 ml. ofabsolute methylene chloride. The reaction mixture is refluxed for "150minutes and'then cooled to 0; to the obtained solution of1-butyl-3,3-bis-(2-hydroxyethyl)-urea is then added dropwise during 1hour, a solution of 250 g. (2.1 moles) of thionyl chloride in 250- ml.of absolute methylene chloride. The reaction mixture is then refluxedfor 4 hours; it is afterwards concentrated in vacuo, and the residue,crude 1-butyl-3,3-bis-(2-chloroethyl)-urea, dried for 8 hours" at 70-80"under high vacuum.

bro'mobenzeneis slowly added dropwise, atire terriperature, to 2.5 g.(0. 1051noles) of activatedimagnfu'rn chipsjin 100 ml. of absolute etheThe reactio mixture isboiled until practically all the magnesium isconsumed; the mixture is then cooled to and a solution 19' 4 g. (0.1mole) of ,l-[

. EXAMPLE-9, (a) 22.6 g. (0.1 mole) of 1-[2-(1-piperazinyl) ethyl[-3,4-dimethyl-2-imidazolidinone, 30.0 g. (0.15 moles) of4-chloro-4'-fiuorobutyrophenone,27.6 g. (0.20rnoles) of potassiumcarbonate and 16.6 g. (0.1 mole) of potassium iodide areintroduced'into' 200 ml. of diethyl ketone-and, with good stirring,refluxed for 24 hours. The lio't -r'eaction mixture is filtered throughCelit the residue boiled out twice with acetone, and filtered. Thecombined filtrates are concentratedin vacuo, and the oily residue isdissolvedin 200 ml. of benzene. After the addition of -10 ml. of 2 Nsodium hydroxide solution, the benzene .solution is extracted threetimes with 100; ml.. of water veachtime. The organic phase issubsequently extracted with 200 ml. of 2 N- hydrochloric acid; the.aqueous acid extractiare rendered strongly alkaline (pH 13)withconcentrated sodium hydroxidesolution, and again extracted withbenzene. The organic solutions are washed with water, dried overmagnesium sulphate and concentrated in vacuo to dryness. Theobtainedcrystalline residue is recrystallized from ether/pentane, whereupon the.obtained pure1-[2-[4-[3-(p-fluorobenzoyl)-propyl].-1-piperazinyl]-ethyl]-3,4-dimethyl-Z-imidazolidinonemelts at 73-74".

The dihydrochloride is obtained analogously to,Ex- F ample 1, MP.228235. I t

The l- 2- (piperazinyl -ethyl] -3,4-dimethyl-2-imidazolidinone requiredas starting material is produced as follows: 1 (b) Anamount of 17.8 g.(0.2 moles) of rac. 2-methylamino-l-propanol is dissolved in 30 ml.of.:methy-l ene chloride; to this solution is then added dropvvise at 0a solution of 23.2 g. (0.22 moles) of 2-chloroethylisocyan- .ate in 50ml. of methylene chloride. The reaction mixture is stirred for 2 hoursat room temperature, concentrated in vacuo to dryness, andthecrystallized residue recrystallized from ether. The obtained 1-,(,2-hydroxy-lmethyl ethyl)-1-methyl-3-(2-chloroethyl)-urea melts 'at76-78.

(0) An amount of 33.4 g. (0.172 moi sj mefia- .tained urea is dissolvedin 80 ml. of chloroform; ,to the .The obtained roily residue isdistilledrin a watenjet vacuum to obtain 1-(2-chloroethyl)-3,4dimethy112- imidazolidinone,rB.P.' 151-153"; n =1.4s1, 1. ,1. =1(d),from 18.8 g..(0.107 mo1es)'0f 1-(2,-.Ghlor ethyl)- 3,4vdimethyl-2-imidazolidinone an d18.5.g.v (0.117 moles) oflepiperazinecarboxylie acid ethyl. ester. are obtaiued analogously toExample 3(b), 26.7. g..of 1 -.[2-;(2 oxo- 3,4-dimethyl-1 rimidazolidinyl) .-..ethyl]spiperazinecarboxylic acid ethyl ester; ..B.P.l70..18Q/ 0,0ltorr; n=1.4968. From this are obtained, analogously. toExample 3(c), 18.2 ,g. or 1-[2- 1- i erazin 1 ems/1173;441-

methyl. z. iimidazolidinone; YB.P. 1301344091493;

I EXAM LE (a Anamount' of 175 (0.1 mole) feri e ql d em 2: 9 ,a abe la athereof.

.- idinone dihydrochloride dihydrate melts L A compound of the formula IR is an alkyl group having l'to "4 carbon atoms,

[3 '(p'-fluo"r obenzoyl)-propyl]'1-piperazinyl] 3 methyl2-imidazolidinone' or a "ceptable acid addition salt, thereof.'""iSJ'The'dihydrochloride salt of the" 6f 1 [4 f "[3 (p'fluorobenzoyD-propyl] -lpiperazinyl]' -etl;1 yl]- "3-ethyl 2imidazlidinone'or a pharmaceutically acceptable Q 7 lams-s.

'12 tetrahydrofuran, is added dropwise within 30 minutes. The obtainedreaction mixture is refluxed for1 2'hour's, and "afterwards pouredon toa mixture of 200ml of ice water and ml. of 2 N hydrochloric acid.Theobtained acid mixture is allowed tostand fornonlenhou'r at roomtemperature, and subsequently carefully concentrated at-40 in vacuo to avolume of 200 The obtained solution is diluted with water, and"extracted with ether. The aqueous phase is separated, renderedalkalinewith concentrated ammonia, and extracted three by being shaken withbenzene. The benzene extracts are washed with water, dried overmagnesium sulphatd fiud concentrated in yacuo to dryness.;-'I:he.obtainedfcrystalline residueis dissolved .in beuzene, and the. solo onfiltered through magnesium silicate WOeImPIITheeIIiate isconcentrated byevaporation, and the residue recrystallliz edfro'rri ethylacetate/petroleum ether, The obtained .azinyl]-etliyl]3-methyl-2-imidazolidinone at methyl-Z-imidazolidinone required asstarting niaterial is wpr oduced as follows:

'(b) Anamount of 21.2 g. 0.l,mole) of 1 [2 (1- piperazinyD-ethyl]-3methyl-2-imidazolidinorie is'fre- -fluxed with 12.6 g. (0.13 moles of.4-chlorobu'tyronitrile land 27.6 g. (0.21 moles) of. potassium carbonatein 250 ml. of diethyl ketone for 24 hours. Thef obtained mixture isfiltered through Celit, and thefilter residue wllashe d put withacetone; the combined filtrates are dried ,Imagnesium sulphate, andsubsequently concentrated in vacuo to dryness. The obtained oily residueis dissolved in ethyl acetate, and the hydrochloride precipitated withethanolic hydrochloric acid. After recrystallization from ethanol/ethylacetate, the obtained pure 1-[2-[4-(3-cyanopropyl)-1,piperazinyl]-ethyl]-3-methyl Z-imidazol- .What is claimed is: v V

'GHr-CHs wherein A is an alkylene group having2..carbon atoms,

, Ai'is an alkylene group having 2,to 4 carln'm atoms,

Ri'ishydro gen', or an a ky group having 1 .4 9

he pliarmac'eutically acceptable" acid addition salts The compoundaccording-to claim I which is" v 1 aeaw iaa yacompound according toclaim 1) whiclriis 1"-[ acid addition salt thereof.

5. The ":dihyd rochloride" salt of the claim4. Y

6. The compound .accordingtovclaim 1 which is 1-[2- '3-n butyl2-imidazolidinone or a pharmaceuticall acceptableacidaddition saltthereof. I I The"IdihydrochlOIidQT$2 0f 8. The Compound according toclaim 1 which is l-[3- [4 [3 (p fluorobenzoyl) propyl]-1-piperazinyl]-propyl] 3 methyl 2 imidazolidinone or a pharmaceutically acceptable acidaddition salt thereof.

9. The bis-maleate salt of the compound of claim 8.

10. The compound according to claim 1 which is 1-[2- [4 [3(p-fluorobenzoyl)-propyl]-1-piperazinyl]-ethyl]-3-isopropyl-Z-imidazolidinone or a pharmaceutically acceptable acidaddition salt thereof.

11. The dihydrochloride salt of the compound of claim 10.

12. The compound of claim 1 which is 1-[3-[4-[3-(pfluorobenzoyl) propyl]l-piperazinyl]-propyl]-3-ethyl- 2-imidazolidinone or a pharmaceuticallyacceptable acid addition salt thereof.

13. The dihydrochloride salt of the compound of claim 12.

14 References Cited UNITED STATES PATENTS 2,985,657 5/1961 Janssen260-268 H 3,000,892 9/1961 Janssen 260-268 R 3,320,247 5/1967 Arnold260-268 H 3,637,704 1/ 1972 Umeomoto 260-268 R 3,646,037 2/1972Schindler et a1. 260-268 H 3,658,821 4/1972 Fauran et al. 260-268 R3,699,107 10/ 1972 Schindler et a1. 260-268 H DONALD G. DAUS, PrimaryExaminer US. Cl. X.R.

